tbuckley/cabot-search huggingface dataset:
BACE1 regulates expression of Clusterin in astrocytes for enhancing clearance of β-amyloid peptides
Authors: John Zhou, Neeraj Singh, James Galske, Jacob Hudobenko, Xiangyou Hu, Riqiang Yan
Journal: Molecular Neurodegeneration (2023)

Abstract Background Abnormal accumulation of amyloid beta peptide (Aβ) in the brain induces a cascade of pathological changes in Alzheimer’s disease (AD), and inhibiting BACE1, which is required for Aβ generation, is therefore being explored for the treatment of AD by reducing Aβ accumulation. As Bace1 knockout mice exhibit increased number of reactive astrocytes and AD brains have reactive astrocytes that surround amyloid plaques, we investigated the role of BACE1 in astrocytes and determined whether BACE1 regulates astrocytic functions. Methods We conducted unbiased single cell RNA-seq (scRNA-seq) using purified astrocytes from Bace1 KO mice and wild type control littermates. Similar scRNA-seq was also conducted using AD mice with conditional deletion of Bace1 in the adult stage ( 5xFAD;Bace1 fl/fl ;UBC-creER compared to 5xFAD;Bace1 fl/fl controls). We compared the transcriptomes of astrocyte and reactive astrocyte clusters and identified several differentially expressed genes, which were further validated using Bace1 KO astrocyte cultures. Mice with astrocyte-specific Bace1 knockout in 5xFAD background were used to compare amyloid deposition. Mechanistic studies using cultured astrocytes were used to identify BACE1 substrates for changes in gene expression and signaling activity. Results Among altered genes, Clusterin ( Clu ) and Cxcl14 were significantly upregulated and validated by measuring protein levels. Moreover, BACE1 deficiency enhanced both astrocytic Aβ uptake and degradation, and this effect was significantly attenuated by siRNA knockdown of Clu . Mechanistic study suggests that BACE1 deficiency abolishes cleavage of astrocytic insulin receptors (IR), and this may enhance expression of Clu and Cxcl14 . Acutely isolated astrocytes from astrocyte-specific knockout of Bace1 mice ( Bace1 fl/fl ;Gfap-cre ) show similar increases in CLU and IR. Furthermore, astrocyte-specific knockout of Bace1 in a 5xFAD background resulted in a significant attenuation in cortical Aβ plaque load through enhanced clearance. Conclusion Together, our study suggests that BACE1 in astrocytes regulates expression of Clu and Cxcl14 , likely via the control of insulin receptor pathway, and inhibition of astrocytic BACE1 is a potential alternative strategy for enhancing Aβ clearance.
The “echo-free space” technique: a safe and reliable method for endoscopic ultrasound scope insertion
Authors: Shunsuke Omoto, Mamoru Takenaka, Tomohiro Fukunaga, Kota Takashima, Yoriaki Komeda, Seok Jeong, Masatoshi Kudo
Journal: Endoscopy (2023)

In recent years, the applications of endoscopic ultrasound (EUS) have expanded greatly, not only as an observational tool but also as a treatment procedure such as with EUS-guided fine-needle aspiration (FNA) and EUS-guided drainage [1] [2] [3] [4].
Peroral cholangioscopy-guided transpapillary gallbladder drainage and cholecystolithotomy in the treatment of acute cholecystitis and cholelithiasis
Authors: Xiao-gang Liu, Xin-yu Huang, Rui Huang, Ren-yi Zhang, Wei-hui Liu
Journal: Endoscopy (2023)

A 35-year-old pregnant woman presented with upper right abdominal pain and jaundice. Laboratory analysis showed leukocytosis, elevated C-reactive protein, hypertransaminasemia, and cholestasis. Endoscopic ultrasonography (EUS) revealed cholecystolithiasis, acute cholecystitis, and suspected choledocholithiasis ([Fig. 1]). The patient was referred for endoscopic retrograde cholangiopancreatography (ERCP) treatment for gallbladder drainage and choledocholithiasis removal ([Video 1]).
Cardiometabolic multimorbidity, lifestyle behaviours, and cognitive function: a multicohort study
Authors: Yinzi Jin, Jersey Liang, Chenlu Hong, Richard Liang, Yanan Luo
Journal: The Lancet Healthy Longevity (2023)

Little is known about the effect of lifestyle factors on cognitive decline related to cardiometabolic multimorbidity. We aimed to examine the association between cardiometabolic multimorbidity and cognitive decline, and the role of lifestyle factors in this association.We did a pooled multi-cohort study using pooled data from four cohort studies (the Health and Retirement Study; the English Longitudinal Study of Ageing; the Survey of Health, Ageing and Retirement in Europe; and the China Health and Retirement Longitudinal Study) across 14 countries. Eligible participants were age 50 years and older, and those who were missing information on exposure and outcomes, or who had been diagnosed with dementia or Parkinson's disease, were excluded. Cardiometabolic multimorbidity was defined as the co-occurrence of two or three cardiometabolic diseases, including diabetes, heart disease, and stroke. The primary outcome of cognitive function was measured in three domains, on the basis of the mean and SD of the corresponding tests: memory, numeracy, and orientation, in all participants with available data. A global cognitive score was created by summing the individual scores.The final sample consisted of 160 147 individuals across all four studies (73 846 [46·1%] men and 86 301 [53·9%] women) and participants had a mean age of 67·49 years (SD 10·43). An increasing number of cardiometabolic diseases was dose-dependently associated with the decline in cognitive function score (one disease, β=-0·15 [95% CI -0·17 to -0·13]; two diseases, β=-0·37 [-0·40 to -0·34]; three diseases, β=-0·57 [-0·64 to -0·50]), with comorbid diabetes and stroke (β=-0·23 [-0·29 to -0·17]) contributing most strongly to cardiometabolic disease-associated cognitive decline. Cognitive decline associated with cardiometabolic disease was accelerated with physical inactivity (one cardiometablic disease, p=0·020; two cardiometablic diseases, p=0·42; and three cardiometablic diseases, p=0·24), excessive alcohol use (one cardiometablic disease, p=0·016; two cardiometablic diseases, p=0·65; and three cardiometablic diseases, p=0·50), and the higher number of unhealthy lifestyle factors (one cardiometablic disease, p=0·79; two cardiometablic diseases, p=0·0050; and three cardiometablic diseases, p=0·888).These findings indicated a targeted approach for simultaneously developing preventative interventions on lifestyles and integrated treatment for cardiometabolic comorbidities to delay cognitive decline in older people.Major Project of the National Social Science Fund of China, National Natural Science Foundation of China, China Medical Board, and Young Elite Scientists Sponsorship Program by CAST.
Gel immersion radial incision and cutting for pancreaticojejunostomy anastomotic stricture
Authors: Nozomi Okuno, Kazuo Hara, Shin Haba, Takamichi Kuwahara, Yasuhiro Kuraishi, Takafumi Yanaidani
Journal: Endoscopy (2023)

Pancreaticojejunostomy anastomotic stricture (PJAS) is a late adverse event after pancreaticoduodenectomy [1] that can lead to pancreatic stones, pancreatitis, and abdominal pain. Radial incision and cutting (RIC) has shown promising results for esophagogastric stricture [2], and its usefulness for refractory PJAS was reported in 2021 [3]. However, there have been only a few cases, and the procedure remains challenging. The advantages of gel immersion endoscopy using a clear gel (VISCOCLEAR; Otsuka Pharmaceutical Factory) have been reported for securing a good visual field, including in endoscopic submucosal dissection [4]. Here, we report a case of PJAS treated by RIC during gel immersion endoscopy.
Rare complications related to lumen-apposing metal stent placement, successfully treated by endoscopic hand-suturing device.
Authors: Yosuke Minoda, Nao Fujimori, Mitsuru Esaki, Shuzaburo Nagatomo, Yasuhiro Komori, Keijiro Ueda, Eikichi Ihara
Journal: Endoscopy (2023)

A 56-year-old man with a walled-off necrosis (WON) underwent endoscopic necrosectomy using a lumen-apposing metal stent (LAMS) (Hot Axios; Boston Scientific, Boston, Massachusetts, USA) ([Fig. 1 a]), which improved the abdominal inflammation within 1 month. However, 1 year after removal of the LAMS, the WON relapsed with abdominal pain and elevated C-reactive protein (CRP) levels. Gastroscopy revealed that the fistula caused by the LAMS placement persisted, with leakage of necrotic material. Fluoroscopy also revealed a colonic fistula associated with the WON in the sigmoid colon ([Fig. 1 b]). An ileostomy, in combination with drainage using a plastic stent into the WON and administration of antibiotics, failed to improve abdominal symptoms and normalize CRP levels; this was suggested to be attributed to the two fistulas. After percutaneous drainage of the WON, an over-the-scope (OTS) clip was applied to close these fistulas. However, the colon and gastric tissues around the fistula were too rigid to be pulled in the OTS clip. In this situation, we attempted to close the gastric fistula using a new endoscopic hand-suturing device (SutuArt; Olympus, Tokyo, Japan) and a suture needle with thread (V-lock; Medtronic, Dublin, Ireland) after cauterization of the gastric mucosa surrounding the fistula to promote wound healing ([Fig. 1 c–g], [Video 1]). One month later, the fistula was completely fixed with a normal covered mucosa ([Fig. 1 h]). This led to an improvement in abdominal pain and CRP levels.
Defect closure with endoscopic suturing improves endoscopic full-thickness resection of duodenal gastrointestinal stromal tumors
Authors: Chu-Kuang Chou, Chien-Chuan Chen, Chi-Ming Tai, Kun-Feng Tsai, Chung-Ying Lee, Ding-Ek Toh, Sheng-Shih Chen
Journal: Endoscopy (2023)

Endoscopic resection of duodenal gastrointestinal stromal tumors (GISTs) is challenging with non-negligible complications [1]. Endoscopic full-thickness resection (EFTR) is usually required [2] but remains uncommon for unsatisfactory defect closure. Clip-based methods are challenging for closing large defects and can be improved with mucosal flap preservation, which is time-consuming [3]. The strong and reliable whole-layer approximation with endoscopic suturing can change the decision-making of EFTR [2] [4] [5].
A novel cannula with a movable tip facilitates cannulation during endoscopic retrograde cholangiopancreatography in reconstructed intestinal tracts
Authors: Tsuyoshi Suda, Satoko Inagaki, Saiho Sugimoto, Kiichiro Kaji, Shuichi Terasaki
Journal: Endoscopy (2023)

An 83-year-old woman was admitted with obstructive jaundice. She was diagnosed with pancreatic head cancer after a close examination ([Fig. 1]). She had previously undergone total gastrectomy with Roux-en-Y reconstruction and caudal pancreatectomy for pancreatic body cancer. Thus, we attempted to treat the obstructive jaundice via endoscopic retrograde cholangiopancreatography (ERCP) using a short-type single-balloon enteroscope.
EvoAug: improving generalization and interpretability of genomic deep neural networks with evolution-inspired data augmentations
Authors: Nicholas Keone Lee, Ziqi Tang, Shushan Toneyan, Peter K. Koo
Journal: Genome biology (2023)

Deep neural networks (DNNs) hold promise for functional genomics prediction, but their generalization capability may be limited by the amount of available data. To address this, we propose EvoAug, a suite of evolution-inspired augmentations that enhance the training of genomic DNNs by increasing genetic variation. Random transformation of DNA sequences can potentially alter their function in unknown ways, so we employ a fine-tuning procedure using the original non-transformed data to preserve functional integrity. Our results demonstrate that EvoAug substantially improves the generalization and interpretability of established DNNs across prominent regulatory genomics prediction tasks, offering a robust solution for genomic DNNs.
3D printed implantable drug delivery devices for women’s health: Formulation challenges and regulatory perspective
Authors: Karen Al-Litani, Tariq Ali, Pamela Robles Martinez, Asma Buanz
Journal: Advanced Drug Delivery Reviews (2023)

Modern pharmaceutical interventions are shifting from traditional "one-size-fits-all" approaches toward tailored therapies. Following the regulatory approval of Spritam®, the first marketed drug manufactured using three-dimensional printing (3DP) technologies, there is a precedence set for the use of 3DP in the manufacture of pharmaceutical products. The involvement of 3DP technologies in pharmaceutical research has demonstrated its capabilities in enabling the customisation of characteristics such as drug dosing, release characteristics and product designs on an individualised basis. Nonetheless, research into 3DP implantable drug delivery devices lags behind that for oral devices, cell-based therapies and tissue engineering applications. The recent efforts and initiatives to address the disparity in women's health is overdue but should provide a drive for more research into this area, especially using new and emerging technologies as 3DP. Therefore, the focus of this review has been placed on the unique opportunity of formulating personalised implantable drug delivery systems using 3DP for women's health applications, particularly passive implants. An evaluation of the current landscape and key formulation challenges for achieving this is provided supplemented with critical insight into the current global regulatory status and its outlook.
The Prognostic Effect of IKZF1 Deletions in ETV6::RUNX1 and High Hyperdiploid Childhood Acute Lymphoblastic Leukemia
Authors: Anna Østergaard, Amir Enshaei, Rob Pieters, Ajay Vora, Martin A. Horstmann, Gabriele Escherich, Bertil Johansson, Mats Heyman, Kjeld Schmiegelow, Peter M. Hoogerbrugge, Monique L. den Boer, Roland P. Kuiper, Anthony V. Moorman, Judith M. Boer, Frank N. van Leeuwen
Journal: HemaSphere (2023)

IKZF1 deletions are an established prognostic factor in childhood acute lymphoblastic leukemia (ALL). However, their relevance in patients with good risk genetics, namely ETV6 :: RUNX1 and high hyperdiploid (HeH), ALL remains unclear. We assessed the prognostic impact of IKZF1 deletions in 939 ETV6 :: RUNX1 and 968 HeH ALL patients by evaluating data from 16 trials from 9 study groups. Only 3% of ETV6 :: RUNX1 cases (n = 26) were IKZF1 -deleted; this adversely affected survival combining all trials (5-year event-free survival [EFS], 79% versus 92%; P = 0.02). No relapses occurred among the 14 patients with an IKZF1 deletion treated on a minimal residual disease (MRD)-guided protocols. Nine percent of HeH cases (n = 85) had an IKZF1 deletion; this adversely affected survival in all trials (5-year EFS, 76% versus 89%; P = 0.006) and in MRD-guided protocols (73% versus 88%; P = 0.004). HeH cases with an IKZF1 deletion had significantly higher end of induction MRD values ( P = 0.03). Multivariate Cox regression showed that IKZF1 deletions negatively affected survival independent of sex, age, and white blood cell count at diagnosis in HeH ALL (hazard ratio of relapse rate [95% confidence interval]: 2.48 [1.32-4.66]). There was no evidence to suggest that IKZF1 deletions affected outcome in the small number of ETV6 :: RUNX1 cases in MRD-guided protocols but that they are related to higher MRD values, higher relapse, and lower survival rates in HeH ALL. Future trials are needed to study whether stratifying by MRD is adequate for HeH patients or additional risk stratification is necessary.
Effectiveness of endoscopic ultrasound-guided drainage procedure for symptomatic lymphocele
Authors: Koichi Soga, Shun Takakura, Akinobu Sai
Journal: Endoscopy (2023)

A 65-year-old Japanese woman was admitted to our hospital with complaints of abdominal pain and a fever of 39.0 °C. Computed tomography (CT) revealed an infected lymphocele after surgery for ovarian cancer. Endoscopic ultrasound-guided lymphocele drainage (EUS-LD) was planned while avoiding free space between the colon and lymphocele using a convex EUS scope ([Fig. 1]).
Segmental absence of the intestinal musculature in the stomach of an adult found during endoscopic submucosal dissection
Authors: Kohei Funasaka, Noriyuki Horiguchi, Ryoji Miyahara, Tomoyuki Shibata, Yoshiki Hirooka
Journal: Endoscopy (2023)

Segmental absence of intestinal musculature (SAIM) is a rare cause of spontaneous perforation in neonates [1] and is quite rare in adults [2]. Since 2020, SAIM has been reported to cause perforation during endoscopic submucosal dissection (ESD) of the esophagus [3] [4] [5]; however, SAIM has never been reported in the stomach in adults. Herein, we report a case of SAIM identified during gastric ESD.
Clinical significance of defective mismatch repair in endometrial carcinoma
Authors: D. Black, D. A. Levine, F. Bogomolniy, R. R. Barakat, R. A. Soslow, C. Tornos, S. C. Chen, J. Boyd
Journal: Journal of Clinical Oncology (2005)

5021 Background: Defective mismatch repair, manifesting as microsatellite instability (MSI), underlies the pathogenesis of the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, and also occurs in sporadic manifestations of gastrointestinal, endometrial, and other cancers. In colorectal carcinoma, MSI is associated with improved outcome. Here, we test the hypothesis that MSI predicts for the clinicopathologic behavior of endometrial carcinoma. Methods: An unselected series of 473 patients treated for endometrial carcinoma were identified from a single institution. Using a consensus panel of five microsatellite markers, DNA from matched normal and tumor tissue pairs was used to determine the presence of MSI. Tumors were classified as MSI(+) when two or more markers displayed MSI. All cases were reviewed by a gynecologic pathologist and clinical information was abstracted from medical records. Standard two-sided statistical tests were used in all analyses. Results: Of the 473 tumors, 92 (20%) exhibited MSI. There was no statistically significant correlation between the presence of MSI and patient age, surgical stage, or tumor grade. Tumors of endometrioid histology were more likely to display MSI than tumors of non-endometrioid histology (P = 0.001). After a median follow-up of 56 months, the mean disease-specific survival of patients with MSI(+) tumors was 135 months, compared to 122 months for patients with MSI(-) tumors (P = 0.002). In a multivariate analysis, stage, grade, and MSI were independently associated with disease-specific survival. Patients with MSI(+) tumors were more likely to have a first-degree relative with an HNPCC-associated malignancy (P = 0.001). Conclusions: Defective mismatch repair occurs in 20% of all endometrial carcinomas. The presence of MSI in endometrial carcinomas is independently associated with histologic subtype and a more favorable outcome. No significant financial relationships to disclose.
Phase II study of the farnesyl transferase inhibitor tipifarnib plus fulvestrant in postmenopausal patients with hormone receptor-positive breast cancer: New York Cancer Consortium Trial P6205
Authors: T. Li, P. Christos, J. A. Sparano, D. L. Hershman, K. O’Brien, S. Hoschander, J. Wright, L. T. Vahdat
Journal: Journal of Clinical Oncology (2007)

1037 Background: Tipifarnib and fulvestrant both have single agent activity in hormone receptor-positive (HR+) metastatic breast cancer (MBC), and tipifarnib enhances the activity of anti-estrogens in HR+ breast cancer cell lines. Methods: Eligibility criteria: measurable HR+ MBC, postmenopausal status, ECOG PS of 0–2, and no prior chemotherapy for MBC. Treatment: fulvestrant 250 mg IM on day 1 plus oral tipifarnib 300 mg BID on days 1–21 every 28 days (defined as one cycle). Response was evaluated by RECIST criteria every 3 cycles. The study was suspended for efficacy/futility analysis after 33 of 46 patients were accrued. It was designed to detect an improvement in clinical benefit rate (CBR; defined as objective response or stable disease for at least 24 weeks) from 50% to 70% (90% power, type I error 10%), and would require at least 26 of 42 eligible/evaluable patients to have clinical benefit (CB). The expected CBR for fulvestrant alone is 30% in aromatase inhibitor (AI) resistant disease (Ingle, 2006), 45% in tamoxifen (tam)-resistant disease (Osborne, 2002), and 60% when used as first line endocrine therapy (ET) (Howell, 2004). Results: Of 33 patients enrolled, 28 are currently assessable for CBR (2 were ineligible, and 3 have stable disease for &lt; 6 months and remain on treatment). Grade 3/4 toxicity: neutropenia (15%), pain (11%) and gastrointestinal toxicity (11%). Tipifarnib was either reduced in dose (N=10) or discontinued (N=8) due to toxicity or non-compliance. The overall CBR is shown; should accrual continue, all 14 evaluable patients must have CB in order to meet the pre-specified efficacy objective. For the ET-resistant group, 18 were resistant to AI therapy (or AI plus tam in 5) and 2 to tam. * Number eligible/evaluable for CBR. Conclusions: The tipifarnib-fulvestrant combination is not likely to produce a CBR of at least 70%. The 45% CBR in ET-resistant disease may merit further evaluation in this setting. [Table: see text] No significant financial relationships to disclose.
Research with children
Authors: R. L Smyth
Journal: BMJ (2001)

All those concerned with the clinical care of children have a responsibility to improve that care, and one way of achieving this is by research. The importance of research into normal childhood development and into the methods of promoting good health, together with studies of the aetiology, natural history, diagnosis, and treatment of childhood diseases is well recognised. So too are the perils of relying on information from studies conducted in adults and generalising these to children. However, undertaking clinical research in children presents unique challenges.1

The most obvious of these are the ethical ones: the need to protect children from harm while respecting their autonomy and to obtain properly informed consent from parents, and, when possible, the children themselves. There are also methodological challenges. Outcome measures, developed and validated in adults, are unlikely to be appropriate or feasible for children and babies. The proportions of children affected by chronic diseases are smaller and the diseases often more heterogeneous than in adults, and diagnostic …
Expression of growth factor receptors in unilineage differentiation culture of purified hematopoietic progenitors
Authors: U Testa, C Fossati, P Samoggia, R Masciulli, G Mariani, HJ Hassan, NM Sposi, R Guerriero, V Rosato, M Gabbianelli, E Pelosi, M Valtieri, C Peschle
Journal: Blood (1996)